title: Dangers of bone graft substitutes: lessons from using GeneX.
abstract: BACKGROUND
  Bone graft substitutes are widely used in spinal surgery. Here, serious complications associated with the bone graft substitute GeneX are presented. GeneX contains tri-calcium phosphate and calcium sulphate.
  
  
  METHODS
  GeneX was used in three patients who had spinal decompression and fusion. Mice were also injected with GeneX, demineralised bone matrix (DBX) or saline subcutaneously. After 24 h the extent of tissue damage and inflammation in tissue sections was quantified. To understand the licensing process for bone graft substitutes, the U.S. Food and Drug Administration (FDA) and the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) websites were accessed.
  
  
  RESULTS
  All patients developed sterile pus in soft tissues adjacent to the GeneX followed by skin breakdown in two and pharyngeal perforation in one. In mice, GeneX produced moderate or severe skin damage compared with no or mild skin damage after DBX (p<0.05) or saline (p<0.05) injection. GeneX caused more inflammation in mouse dermis (1704±193 leucocytes/mm2, mean ± SE) than DBX (537 ± 266, p<0.01) or saline (136 ± 19, p<0.01). The FDA and MHRA classify bone graft substitutes as medical devices. In contrast with drugs, medical devices do not need to undergo clinical safety tests before obtaining FDA 510(k) clearance for use in patients.
  
  
  CONCLUSIONS
  GeneX may cause soft tissue inflammation and destruction and should not be placed next to thin walled structures, such as skin or pharynx, because it may erode through these tissues. Bone graft substitutes should undergo mandatory detailed safety testing prior to approval. This could be achieved by reclassifying them as drugs.
authors.affiliation: Academic Neurosurgery Unit, St. George's, University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK.
authors.forename: Samira
authors.initials: S
authors.lastname: Saadoun
authors.forename: Claire
authors.initials: C
authors.lastname: Macdonald
authors.forename: B Anthony
authors.initials: BA
authors.lastname: Bell
authors.forename: Marios C
authors.initials: MC
authors.lastname: Papadopoulos
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001857:Bone Matrix / Q000601:surgery; D018786:Bone Substitutes / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism*; D002130:Calcium Phosphates / Q000008:administration & dosage; D002133:Calcium Sulfate / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012867:Skin / Q000378:metabolism*; D013131:Spine / Q000601:surgery*; D016896:Treatment Outcome
chemical_list: D018786:Bone Substitutes; D002130:Calcium Phosphates; C020243:calcium phosphate; D002133:Calcium Sulfate